DO: 0110315;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.2 | Cardiomyopathy, familial hypertrophic, 9 | 613765 | Autosomal dominant | 3 | TTN | 188840 |
A number sign (#) is used with this entry because of evidence that familial hypertrophic cardiomyopathy-9 (CMH9) is caused by heterozygous mutation in the TTN gene (188840) on chromosome 2q31.
For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy (CMH), see CMH1 (192600).
In 1 of 82 patients with hypertrophic cardiomyopathy who had no mutation in known disease genes, Satoh et al. (1999) identified a mutation in the TTN gene (188840.0001) that was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha-actinin (see 102575) in the yeast 2-hybrid assay.
Herman et al. (2012) used next-generation sequencing to analyze the TTN gene in 203 individuals with dilated cardiomyopathy (CMD; see CMD1G, 604145), 231 with CMH, and 249 controls. The frequency of TTN mutations was significantly higher among individuals with CMD (27%) than among those with CMH (1%) or controls (3%). In the 3 patients with CMH in whom TTN truncating or splicing mutations were identified, concurrent analyses revealed a pathogenic mutation in the known CMH genes MYH7 (160760) or MYBPC3 (600958). Herman et al. (2012) suggested that TTN truncations rarely, if ever, cause hypertrophic cardiomyopathy.
Lopes et al. (2013) analyzed the coding, intronic, and regulatory regions of 41 cardiovascular genes in 223 unrelated patients with CMH using high-throughput sequencing technology. They found 219 rare variants in 142 (63.6%) of the patients: 30 patients (13%) had titin candidate variants in isolation, 22 (10%) had titin variants only in association with desmosomal gene candidate variants or ion channel disease-associated variants, and 171 (77%) carried a TTN candidate variant in association with sarcomere, Z-disc, or calcium-handling gene variants. Lopes et al. (2013) noted that titin has been difficult to sequence and study due to its size, large number of isoforms, and unsolved tertiary structure. All of the individual variants present in this cohort occurred with a frequency of less than 0.5% in the 1000 Genomes Project, suggesting that a proportion of them might be, at the very least, modulators of the phenotype. However, the overall frequency of variants in the CMH cohort was actually lower than that seen in the control exome population. Lopes et al. (2013) concluded that further work on understanding the role of titin in CMH was necessary.
Herman, D. S., Lam, L., Taylor, M. R. G., Wang, L., Teekakirikul, P., Christodoulou, D., Conner, L., DePalma, S. R., McDonough, B., Sparks, E., Teodorescu, D. L., Cirino, A. L., and 17 others. Truncations of titin causing dilated cardiomyopathy. New Eng. J. Med. 366: 619-628, 2012. [PubMed: 22335739] [Full Text: https://doi.org/10.1056/NEJMoa1110186]
Lopes, L. R., Zekavati, A., Syrris, P., Hubank, M., Giambartolomei, C., Dalageorgou, C., Jenkins, S., McKenna, W., Uk10k Consortium, Plagnol, V., Elliott, P. M. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J. Med. Genet. 50: 228-239, 2013. [PubMed: 23396983] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101270]
Satoh, M., Takahashi, M., Sakamoto, T., Hiroe, M., Marumo, F., Kimura, A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem. Biophys. Res. Commun. 262: 411-417, 1999. [PubMed: 10462489] [Full Text: https://doi.org/10.1006/bbrc.1999.1221]